Anthropoid primate–specific retroviral element THE1B controls expression of CRH in placenta and alters gestation length
| Autor: | Lisa M. Muglia, Kayleigh A. Swaggart, Mihaela Pavlicev, Katherine Young Bezold Lamm, Elizabeth Huffman, Gernot Wolf, Shivani Tumukuntala, Yueh-Chiang Hu, Todd S. Macfarlan, Sandra P. Zoubovsky, Helen Jones, Louis J. Muglia, Ming-an Sun, Amrita Mukherjee, Caitlin E. Dunn-Fletcher, Xuzhe Zhang, Katri Thiele |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Embryology Molecular biology Corticotropin-Releasing Hormone Placenta Gene Expression Artificial Gene Amplification and Extension Syncytiotrophoblasts Polymerase Chain Reaction Sequencing techniques 0302 clinical medicine Short Reports Pregnancy Mobile Genetic Elements Gene expression Medicine and Health Sciences Biology (General) Mammals Mammalian Genomics General Neuroscience DLX3 Eukaryota RNA sequencing Animal Models Genomics Haplorhini Long terminal repeat 3. Good health medicine.anatomical_structure Experimental Organism Systems Vertebrates Female Anatomy General Agricultural and Biological Sciences hormones hormone substitutes and hormone antagonists Primates endocrine system QH301-705.5 Transgene Mouse Models Biology Research and Analysis Methods General Biochemistry Genetics and Molecular Biology Andrology 03 medical and health sciences Model Organisms Genetic Elements Genetics medicine Animals Humans Transcription factor General Immunology and Microbiology Endogenous Retroviruses Organisms Transposable Elements Reproductive System Biology and Life Sciences Molecular biology techniques 030104 developmental biology Animal Genomics Amniotes Homeobox 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 16, Iss 9, p e2006337 (2018) |
| ISSN: | 1545-7885 |
| Popis: | Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5′ insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth. Author summary The proper timing of delivery is critical during pregnancy; if too early or too late, the baby will be at risk of serious health problems and even death. Corticotropin-releasing hormone (CRH) is a protein that can be detected in maternal blood, and its concentration correlates with the timing of birth. In humans and other anthropoid primates, CRH is made by the placenta, whereas in other mammals, it is produced in a specialized region of the brain. To understand the regulation and evolution of this key protein, we inserted the human CRH gene and nearby regions into the mouse genome, which resulted in human CRH expression in the mouse placenta. Mouse litters that make CRH in their placentas are born later than control mice, showing that CRH can directly affect birth timing. Using our mouse model, we then selectively deleted a remnant of an ancient retrovirus that is normally found in the DNA of anthropoid primates and demonstrated that this specific region controls expression of CRH in the placenta. Deletion of this region also restored normal birth timing in the mice by eliminating CRH production from the placenta. We propose that retroviral regulation of CRH in the placenta may be a mechanism of controlling birth timing in humans and other anthropoid primates. |
| Databáze: | OpenAIRE |
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